Unravelling dynamics of microbiota-dependent gene expression and chromatin remodelling in intestinal epithelium and liver

Abstract

The crosstalk between the gut microbiota and host metabolism is a complex and critical process for normal physiology. The intestinal epithelial cells play a fundamental role in this relationship, building mucosal barriers, secreting immunological mediators, and providing bacterial antigens. Furthermore, the microbiome's metabolites also directly affect these cells, driving host metabolism and development. The gut and liver are closely connected, and imbalances in the gut microbiota and bile acids can lead to homeostatic perturbations. The microbiota-host interaction also has implications for epigenetic regulation, with short-chain fatty acids and metabolic products from bile playing a crucial role in this process. Our preliminary data demonstrated antibiotic-induced microbiota depletion's effects on intestinal cells' transcriptional profile. We observed global responses in barrier function and absorption among different cell types, highlighting the impact of dysbiosis on intestinal function. The microbiota was found to impair the cell cycle progression and modulate enteroendocrine cell activity, which produces hormones involved in nutrient absorption and immune response. We also identified specialized enterocytes and a hybrid cell phenotype with absorptive and secretory functions. Histone acylations, such as crotonylation, emerged as a potential mediator of microbiota-chromatin signaling, with varying levels of crotonylated gene expression across different cell types. Dysbiosis's specific effects on the liver-gut axis and the role of epigenetic modifications, particularly crotonylation and related modifications, warrant further investigation. To achieve our objectives, we plan to integrate scRNA-seq datasets, map chromatin accessibility, and explore different microbiome compositions and recovery processes. Overall, our study sheds light on the intricate relationship between microbiota, cellular function in the gut and liver, and epigenetic regulation, paving the way for a better understanding of host-microbe interactions and potential therapeutic interventions. (AU)